The main objective of this renewal proposal is to study the natural history of congenital and perinatal cytomegalovirus (CMV) infections in mothers, infants and children by large scale, prospective, longitudinal investigations. Both primary and recurrent maternal infections will be contrasted with regard to intrauterine and perinatal transmission of virus, ability to infect the placenta, and as causes for virulence of the fetal infection. Influence of gestational age on these same parameters will be assessed. The long-term neuropsychological aspects of subclinical and clinically apparent congenital CMV infection will be further assessed and high risk factors for brain damage will be sought using cerebrospinal fluid findings (virologic and immunologic) and radiologic brain imaging technics. Children in the home and sexual transmission will be investigated as to the roles in horizontal transmission to pregnant women. Correlative studies in the serial cellular and humoral immune response to CMV will be continued in various infected populations (primary and recurrent CMV infection in pregnant women, subclinical and clinically apparent congenital and perinatal infections, and normal controls). Cellular immune studies will focus on the lymphocyte blastogenic response to CMV, natural killer cell activity and T cell cytotoxicity. Serial isotype and subclass IgG antibody responses to CMV encoded proteins will be determined in the aforementioned populations and, along with the cellular immune responses, related to transmission of virus in utero, virulence of the congenital infection and persistence of viral excretion. Breast milk humoral immunity will be further dissected and related to reactivation of CMV in the breast and transmission of infections to the offspring via infected breast milk. Molecular studies on the structure and function of the proteins of CMV will continue in order to better understand their relative immunogenicity in humans. All of the projects in this program are interrelated so that the epidemiologic, clinical, pathologic, virologic and immunologic findings can be correlated, thus, providing a broad view of the natural history of CMV in pregnancy and early life.